Electron-rich carbocycle

Quinazolines containing an electron-rich carbocyclic ring have been associated with smooth muscle relaxant activity. The mechanism of action (phosphodiesterase inhibition, a- adrenergic blockade) and organ selectivity (bronchi, vascular smooth muscle) vary greatly with substitution on the heterocyclic ring. 

The Vilsmeier-Haack reagent, a chloroiminium salt, is a weak electrophile. Therefore, the Vilsmeier-Haack reaction works better with electron-rich carbocycles and heterocycles. 

The Vilsmeier-Haack reaction of electron-rich carbocyclic aromatic compounds (Ar—H) with chloromethyleneiminium salt (1) gives aldehyde derivatives (Ar—CHO), generally in good yield. The intermediate iminium salt (cf. salt 5 Scheme 1) can be treated with hydroxylamine to obtain nitrile derivatives (Ar—CN). Benzene and naphthalene are not sufTiciently electron rich to participate in the Vilsmeier-Haack reaction, but polycyclic hydrocarbons, such as anthracene, do react. Benzene and naphthalene derivatives that possess an electron-releasing substituent (—OMe,—SMe,—NMe2, etc.) af-... 

The Vilsmeier-H2iack reagent, a chloroiminium salt, is a weak electrophile. Therefore, the Vilsmeier-Haack reaction works better with electron-rich carbocycles and heterocycles. Since pyrrole is very electron-rich, the Vilsmeier-Haack reaction readily takes place. Formylation of methyl pyrrole-2-carboxylate was achieved using the Vilsmeier-Haack reaction. The mechanism is shown below. The resulting methyl 5-formylpyrrole-2-carboxylate, in turn, was converted into nonpeptidic analogues of neurotesin(8-13), which are potential treatment for neuropsychiatric diseases such as schizophrenia and Parkinson s disease. 

In many ways, the electron-rich five-membered aromatic heterocycles behave very much like carbocyclic aromatic compounds when it comes to lithiation. Lithiation a to O or S of furan and thiophene is straightforward (Scheme 130) . The usual selection of orf/io-directing groups allows lithiation at other positions and some examples... 

Intermolecular Allylboration. A tandem aza[4+2] cycloaddition/allyl-boration three-component reaction has been designed based on the prece-dented carbocyclic [4- -2] cycloaddition/allylboration and a snbsequent one-pot variant. Thns, the thermal reaction between hydrazonobutadienes 138, A-substitnted maleimides, and aldehydes provides polysnbstituted a-hydroxy-alkylpiperidines 141 via the cyclic allylboronate intermediate 139 and the proposed chairlike transition stmctnre 140 (Eq. 103). Monoactivated dienophiles like acrylates fail to react with heterodienes 138 bnt the scope of aldehydes is very broad both ahphatic and aromatic aldehydes are snitable, inclnding electron-rich ones. An inverse electron-demand variant to access the corresponding dihy-dropyran derivatives via the intermediacy of enantiomerically enriched pyranyl allylic boronate 76 has been snbsequently developed (see Eq. 64). ° ... 

Angular momentum arguments show that the Jt-electron-rich nature of (4 +2) SN heterocycles is the key to their diatropic current. Formal expansion of (4 +2)-Jt-carbocyclic systems by insertion of NSN motifs in every CC bond is predicted to lead to structures that support diatropic ring currents explicit ab initio calculation of magnetic response predicts the 24-center, 30n-electron heterocycle S6N12(CH)6, formally derived from benzene, to be aromatic on the basis of this criterion <2002JA11202>. 

Electron-rich heterocycles, such as pyrrole and furan, bear more resemblance to carbocyclic rings their side chains are much less acidic, and undergo lateral lithiation much less readily. Without a second directing group, methyl groups only at the 2-position of furan, pyrrole or thiophene may be deprotonated. 

Four-membered carbocycles Compounds with sufficiently electron-rich olefinic double bonds react with TCNE to yield tetracyanocyclobutyl derivatives by [2 + 2] cycloadditions. Thus 1-vinylpyrazoles 369" as well as 4-vinyl-pyrazoles 371" react to yield the corresponding substituted tetracyanocyclobutanes 370 and 372, respectively. The same reaction has been observed with 1-vinylindazoles". ... 

Another strategy for annelation of pyrroles and indoles involves cycloaddition reactions. Because the heteroaromatic rings have substantial aromatic stabilization, the C2—C3 bond is not very reactive toward cycloaddition and there are only a few examples of the heterocycles acting as dienophiles. The carbocyclic ring of indole, like benzene, is unreactive toward cycloaddition. However, vinylpyrroles and indoles are quite reactive and react as electron-rich dienes because of the electron-donating nature of the ring. Other cycloaddition reactions involve the 2,3-dimethylene derivatives of pyrrole and indole, the so-called quinodimethanes, which are very reactive dienes. These intermediates, and more stable synthetic equivalents, are useful in cycloadditions with a variety of dienophiles. 27/-Isoindole, which itself can be thought of as a quinodimethane, is a very reactive diene. 

Intermolecular arylation of carbocyclic arenes are rare. Exceptionally, phenols are easily arylated. As treated in Chapter 3.7.4, the aryl ether 48 is formed by reaction of aryl halides with hydroquinone monomethyl ether when bulky and electron-rich phosphines are used, which accelerate reductive elimination. Miura and co-workers found new completely different reactions of phenol with bromobenzene by using Pd(OAc)2, PPhs and CS2CO3 to give the unexpected pentaphenylated product 49 in 58% yield [lb, 15]. 

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